Potassium channels control the function of excitable cells such as neurons, smooth muscle cells and cardiac myocytes. Potassium channel regulation is also important in programmed cell death in a variety of cell types. Although a great deal is understood about the function and acute modulation of potassium channels, little is know about long-term control of potassium channel function. Yet, manipulating potassium channel expression in vascular smooth muscle cells, cardiac myocytes and neurons could be a valuable therapeutic approach for controlling high blood pressure and reducing the incidence of cardiac arrhythmias and epileptic seizures. Here we pursue three aims focused on our ongoing studies of potassium channel expression and activity. Aim 1 will determine how Angiotensin II (Ang II) acts on cardiac myocytes to downregulate Kv4.3 channel expression. Experiments will test the hypothesis Ang II acts via NADPH oxidase- generated reactive oxygen species (ROS) to destabilize the 3' untranslated region of the channel messenger RNA. Aim 2 will determine how a protein and a chemical identified by high throughput screening stimulate Kir2.1 activity. Since total channel expression is unaffected, experiments will focus on whether these two activators affect channel trafficking and function. Aim 3 will determine how voltage-gated potassium (Kv) channel activity is slowly increased as a critical step in apoptosis. We will determine whether phosphorylation triggers insertion of new homomeric Kv2.1 channels in the cell surface. Furthermore, we will test whether native channels found in vascular smooth muscle and the heart are subject to similar regulation. This proposal will reveal fundamental insights into novel physiological, pharmacological and pathological mechanisms that produce long-term regulation of potassium channel activity in the heart, blood vessels and the brain.